One of the various approaches to immunising against infection by Neisseria meningitidis (meningococcus) is to use outer membrane vesicles (OMVs). An efficacious OMV vaccine against serogroup B has been produced by the Norwegian National Institute of Public Health [‘MenBvac™’; e.g. ref. 1] but, although this vaccine is safe and prevents MenB disease, efficacy is limited to the homologous serotype used to make the vaccine.
The ‘RIVM’ vaccine is based on OMVs containing six different PorA subtypes. It has been shown to be immunogenic in children in phase II clinical trials [2].
Reference 3 discloses a vaccine against different pathogenic serotypes of serogroup B meningococcus based on OMVs which retain a protein complex of 65-kDa. Reference 4 discloses a vaccine comprising OMVs from genetically-engineered meningococcal strains, with the OMVs comprising: at least one Class 1 outer-membrane protein (OMP) but not comprising a Class 2/3 OMP. Reference 5 discloses OMVs comprising OMPs which have mutations in their surface loops and OMVs comprising derivatives of meningococcal lipopolysaccharide (LPS). Reference 6 discloses a process for preparing OMV-based vaccines for serogroup A meningococcus.
There have been various proposals to improve OMV efficacy. Reference 7 discloses compositions comprising OMVs supplemented with transferrin binding proteins (e.g. ThpA and TbpB) and/or Cu,Zn-superoxide dismutase. Reference 8 discloses compositions comprising OMVs supplemented by various proteins. Reference 9 discloses preparations of membrane vesicles obtained from N. meningitidis with a modified fur gene. Reference 26 teaches that nspA expression should be up-regulated with concomitant porA and cps knockout. Further knockout mutants of N. meningitidis for OMV production are disclosed in references 26 to 28. In contrast to these attempts to improve OMVs by changing expression patterns, reference 29 focuses on changing the methods for OMV preparation, and teaches that antigens such as NspA can be retained during vesicle extraction by avoiding the use of detergents such as deoxycholate.
The failure of meningococcal OMVs to elicit cross-protection against non-homologous serotypes limits their use as general vaccines, but they can be very useful in epidemic situations where disease is characterised by pathogenic strains that are essentially clonal. Thus the Finlay Institute vaccine (VA-MENGOC-BC™) has been useful in Latin America, where serogroup B disease had been dominated by the P1.19,15 serotype, but has not been effective elsewhere [10]. Similarly, the Chiron MeNZB™ vaccine has been targeted at the epidemic strain (P1.7b,4, known as P1.7-2,4 by recent nomenclature) that has been prevalent in New Zealand since 1991.
Reference 11 discloses vaccine comprising multivalent meningococcal bleb compositions, comprising a first bleb derived from a meningococcal strain with a serosubtype prevalent in a country of use, and a second bleb derived from a strain that need not have a serosubtype prevent in a country of use.
It is an object of the invention to provide further and improved meningococcal OMV preparations.